Back
LYFE SCIENCES
Project: HERA
NM_000059.3:c.9117G>A
p.Pro3039=  ·  BRCA2
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The BRCA2 c.9117G>A (p.Pro3039=) variant has been reported in ClinVar as Pathogenic with expert panel review.

clinvar ↗
2

This variant is rare in population databases, with AF 4.03e-06 (1/248378 alleles) in gnomAD v2.1 and AF 3.72e-06 (6/1613038 alleles) in gnomAD v4.1.

gnomad_v2 ↗ gnomad_v4 ↗
3

In a published RNA study, this variant caused exon 23 skipping in puromycin-treated lymphocytes, supporting an abnormal splicing effect consistent with loss of function.

cspec ↗
4

SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which supports a deleterious splicing effect.

spliceai ↗ cspec ↗
5

In the BRCA2-specific clinical-history likelihood dataset, this variant had an LR of 3.91 in 12 probands, meeting ENIGMA PP4 at supporting strength.

PMID:31853058 ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99061599, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP3039
Hotspots ↗